The present invention relates to certain (R) and (S)-enantiomers of a class of substituted 3-pyridyloxy alkylene azetidin-2-yl compounds having significant activity as analgesics. In addition, some (R)-enantiomers have a surprisingly improved toxicity profile over the corresponding (S)-enantiomer of the same species. In addition to having activity as analgesics, the compounds are also effective in preventing neuronal cell death and are effective in treating or preventing inflammation.
The search for more potent and more effective pain controllers or analgesics continues to be a significant research goal in the medical community. A substantial number of medical disorders and conditions produce pain as part of the disorder or condition. Relief of this pain is a major aspect of ameliorating or treating the overall disease or condition. Pain and the possible allievation thereof is also attributable to the individual patient""s mental condition and physical condition. One pain reliever, or a class, may not be effective for a particular patient, or group of patients, which leads to a need for finding additional compounds or pharmaceuticals which are effective analgesics. Opioid and non-opioid drugs are the two major classes of analgesics (Dray, A. and Urban, L., Ann. Rev. Pharmacol. Toxicol., 36: 253-280, 1996). Opioids, such as morphine, act at opioid receptors in the brain to block transmission of the pain signals in the brain and spinal cord (Cherney, N. I., Drug, 51:713-737, 1996). Opioids such as morphine have abuse and addiction liability. Non-opioids such as non-steroid anti-inflammatory agents (NSAIDs) typically, but not exclusively, block the production of prostaglandins to prevent sensitization of nerve endings that facilitate the pain signal to the brain (Dray, et al, Trends in Pharmacol. Sci., 15: 190-197, 1994.; Carty, T. J. and Marfat, A., xe2x80x9cCOX-2 Inhibitors. Potential for reducing NSAID side-effects in treating inflammatory diseasesxe2x80x9d, In: Emerging Drugs: Prospect for Improved Medicines. (W. C. Bowman, J. D. Fitzgerald, and J. B. Taylor, eds.), Ashley Publications Ltd., London, Chap. 19., pp. 391411). Most of the commonly prescribed or over-the-counter (OTC) NSAIDs are also commonly associated with at one side effect or another, such as stomach ulceration or pain. For example, NSAIDs such as aspirin are also known to cause irritation and ulceration of the stomach and duodenum.
WO 94/08922 describes pyridyl ether compounds which enhance cognitive function. U.S. patent applications Ser. Nos. 08/474,873 and 08/485,537 describe certain substituted pyridyl ether compounds as well as other compounds which also act at the nicotinic acetylcholine receptor to stimulate or inhibit neurotransmitter release. WO 96/31475 describes certain 3-substituted pyridine derivatives which are described as being useful for a variety of disorders as modulators of acetylcholine receptors. While some of these references have alluded to pain control as a potential use of the compounds or analogs recited therein, the Applicants have discovered that a certain narrow class of compounds of formula I shown below have a surprising and unexpected very effective analgesic effect. The Applicants have also found that activity at the nicotinic acetylcholine receptor site (e.g., binding thereto) is not necessarily correlated with a compound""s effectiveness as an analgesic, since some of the compounds having very high binding affinity are ineffective as analgesics. The applicants have further found that some (R)-enantiomer in this series are particularly attractive because of an enhanced safety profile relative to the (S)-enantiomer. The Applicants have also found that the claimed azetidinyl substituted 3-pyridyl methylene ether compounds have enhanced activity over the non-azetidinyl class of known compounds in the treatment of pain as well as the prevention of neuronal cell death and inflammation.